Imidazoline and guanidinium compounds such as clonidine and guanabenz elicit a wide variety of responses in both the central nervous system and peripheral tissues. Although many of these cellular effects are mediated by alpha2-adrenergic receptors, both functional and radioligand binding studies indicate that this class of pharmacologically active compounds interact with a cellular protein (IGRS) distinct from the alpha2- adrenergic receptor. Indeed, IGRS does not recognize catecholamines or other known neurotransmitters but does recognize an endogenous clonidine displacing substance purified from brain suggesting the existence of a previously unidentified hormonal/neurotransmitter-receptor system. Detailed analysis of this system and IGRS is limited by the lack of high- specific activity probes selective for the receptor protein. The continued objectives of this proposal are the synthesis and utilization of functionalized molecular probes for the imidazoline/guanidinium receptive site (IGRS), a potentially important receptor involved in metabolic and cardiovascular regulation. IGRS selective molecules developed during the Phase I study will be modified to generate 1) radiolabeled ligands for cell localization of IGRS 2) a radioiodinated photoaffinity adduct for identification of ligand binding subunit 3) suitable ligand for receptor protein purification. Extensive SAR studies of cirazoline-type molecules will be carried out to generate IGRS specific molecules for functional studies.